The present invention, in some embodiments thereof, relates to peptide agents comprising anti-bacterial properties and to methods of treating diseases using same.
Antibiotics, compounds with selective toxicity against infectious microorganisms, present humanity with enormous benefits and are credited with saving many millions of lives since their introduction in the 20th century. Bacterial antibiotic resistance however, has become one of the most important threats to modern health care. Infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality and increased cost of treatment. Today there is a continuing need for new antibiotics to assist in the management of multiply resistant pathogens (e.g. multiply resistant Staphyloccus aureus or vancomycin-resistant enterococcus) and for methods of sensitizing antibiotic-resistant bacteria to antibiotics.
Over the last few years, a great deal of attention has been focused on toxin-antitoxin modules that are found on the chromosomes of many bacteria including pathogens, including E. coli. Each of these modules consists of a pair of genes, of which generally the downstream gene encodes for a stable toxin and the upstream gene encodes for a labile antitoxin. In E. coli alone, six toxin-antitoxin systems have been described. Among these, the most studied is mazEF, which was the first to be described as regulatable and responsible for bacterial programmed cell death [Aizenman, 1996, Proc. Natl. Acad. Sci. USA, 93, 6059-6063; Engelberg Kulka et al., 2006, PLoS Genetics 2, 1518-1526]. E. coli mazF specifies for the stable toxin MazF, and mazE specifies for the labile antitoxin, MazE. In vivo, MazE is degraded by the ATP-dependent C1pAP serine protease (but not by the proteases C1pXP or Lon). MazF is a sequence-specific endoribonuclease that preferentially cleaves single-stranded mRNAs at ACA sequences. MazE counteracts the action of MazF. Since MazE is a labile protein, preventing MazF-mediated action requires the continuous production of MazE. Thus, any stressful condition that prevents the expression of the chromosomally borne mazEF module will lead to the reduction of MazE in the cell, permitting toxin MazF to act freely. Such conditions include: (i) Briefly inhibiting transcription and/or translation by antibiotics like rifampicin, chloramphenicol and spectinomycin; (ii) Over-production of ppGpp that inhibits mazEF transcription; and iii) DNA damage caused by thymine starvation as well as by DNA damaging agents like mitomycin C, or nalidixic acid. These antibiotics and stressful conditions that are well known for causing bacterial cell death have been found to act through the mazEF module [Hazan et al., 2004, J. Bacteriol. 186, 3663-3669; Sat B. et al., 2001, J. Bacteriol., 183, 2041-2045; Sat B. et al., 2003, J. Bacteriol. 185, 1803-1807].
Additional background art includes U.S. Pat. Appl. No. 20070259813, which teaches peptides with antibiotic-like properties and International patent application PCT No. WO 01/64738 which teaches peptides capable of reacting with aminoglycans and transporting molecules of interest in eukaryotic or prokaryotic cells.